Published on Web 10/29/2005
Enantiospecific Sn(II)- and Sn(IV)-Catalyzed Cycloadditions of Aldehydes and Donor-Acceptor Cyclopropanes Patrick D. Pohlhaus and Jeffrey S. Johnson* Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290 Received August 23, 2005; E-mail:
[email protected] Donor-acceptor (D-A) cyclopropanes are exceptionally useful three-atom building blocks due to their ease of synthesis and high reactivity. The ambiphilic behavior D-A cyclopropanes exhibit toward both electrophiles and nucleophiles has created an extensive array of useful reactions available to organic chemists.1 In this regard, the view of vicinally substituted donor-acceptor cyclopropanes (1) as ring-opened 1,3-zwitterionic equivalents (2) implies chirality loss concurrent with reaction progress (eq 1). The purpose of this communication is to demonstrate the unexpected preservation of optical activity in a new family of Lewis acid-catalyzed cyclopropane/aldehyde cycloadditions and to document experiments supporting an unusual SN2 mechanism accounting for the observed enantiospecificity.
We recently reported a highly diastereoselective synthesis of 2,5disubstituted tetrahydrofurans (rac-4) via the formal Sn(OTf)2catalyzed cycloaddition of aldehydes with D-A cyclopropanes (rac-3) bearing a malonyl diester acceptor group and carbon-based resonance donor substituent (eq 2).2,3 As an extension of this work, we wished to develop an asymmetric version of this new reaction.
Assuming participation of a species such as 2 in the reaction mechanism, it would have been necessary to employ ligand control to effect absolute stereochemical induction. Indeed, Sibi successfully employed this strategy in the cycloaddition of nitrones with cyclopropanes,4 a reaction discovered and developed by Kerr.5 However, our initial control experiment employing cyclopropane (S)-3 (>99% ee),6 benzaldehyde, and Sn(OTf)2 (5 mol %) afforded tetrahydrofuran 4a in 96% ee (eq 3). This unexpected result indicated that the chiral information contained in the cyclopropane was being transferred in the initial bond-forming event, intermediate 2 was not significant, and that ligand control might not be necessary. To investigate this possibility, the substrate scope was evaluated with a number of aldehydes in the presence of catalytic quantities of Sn(OTf)2 (eq 3).
The absolute stereochemical information from the cyclopropane was regularly transferred to the tetrahydrofuran products with high 16014
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J. AM. CHEM. SOC. 2005, 127, 16014-16015
Table 1. Aldehyde Scope in the Lewis Acid-Catalyzed Asymmetric [3 + 2] Cycloaddition of Cyclopropane (S)-3 (eq 3)a entry
R
time (h)
yield (%)b
dr
ee (%)
1 2 3 4 5 6 7 8 9 10
Ph 4-ClPh 4-MeOPh 2-furyl 2-thienyl 4-NO2Phc (E)-CHdCHPh CtCPhd Ete iPre
2.25 4.75 3.5 3.25 3.25 15 3.5 6 1.75 2.5
100 97 99 83 98 91 97 90 100 98
>100:1 >83:1 >84:1 24:1 >92:1 > 52:1 17:1 1.6:1 >36:1 >56:1
96 96 99 99 98 34 99 88 96 96
a Cyclopropane (1.0 equiv), aldehyde (3.0 equiv), Sn(OTf) (5 mol %), 2 23-29 °C. b Isolated yields. c With 20 mol % of Sn(OTf)2 used. d With 10 mol % of Sn(OTf)2 used. e With 5 mol % of SnCl4 used as Lewis acid.
fidelity (Table 1). Only extremely electron-poor aldehydes, which require higher catalyst loading and longer reaction times, gave products of
